EO2401, a novel microbiome-derived therapeutic vaccine for patients with recurrent glioblastoma: ROSALIE study.
Authors: Wolfgang Wick, Ahmed Idbaih, Ghazaleh Tabatabai, María Vieito, Agostina Stradella, François Ghiringhelli, Michael C. Burger, Iris Mildenberger, Ulrich Herrlinger, Mirjam Renovanz, Mehdi Touat, Patrick Y. Wen, Antje Wick, Christophe Bonny, Jan Fagerberg, Cécile Gouttefangeas, Ana Maia, David A. Reardon
Journal: Journal of Clinical Oncology (2022)

2034 Background: EO2401 (EO) was designed to activate existing commensal memory T-cells cross-reacting with tumor associated antigens (TAAs). EO includes microbial-derived, synthetically produced peptides corresponding to HLA-A2 restricted epitopes with molecular mimicry to three TAAs upregulated in glioblastoma (GB), IL13Rα2, BIRC5 and FOXM1, with the CD4 helper peptide UCP2 and the adjuvant Montanide. Pre-clinically EO generates strong immune responses and cross-reactive CD8 cells recognizing the TAAs. Methods: This ongoing Ph 1/2 trial (NCT04116658) investigates EO (SC q2 wks X 4 then q4 wks), EO with nivolumab (3 mg/kg q2 wks; EN), and EN with bevacizumab (10 mg/kg q2 wks; ENB) among four Cohorts (Cs) of pts with GB at first progression after radiotherapy/temozolomide. After the Ph 1 of EO followed by EN (C1), C2 investigated EN without (C2a) or with (C2b) surgery while C3 investigated ENB (population as C2a). Results: Among 40 treated pts (C1 n = 3, C2a n = 23, C2b n = 3, C3 n = 11), median age was 60, 53% male, 40% had KPS 90-100% and 35% had O6-methylguanine DNA-methyltransferase promotor hypermethylated tumors. All evaluable pts demonstrated strong CD8 T-cell ELISPOT responses against the 3 vaccine peptides, with tetramer staining of specific CD8 detected in 24/25 investigated pts after in vitro stimulation and in 19/20 pts directly ex vivo. Cross-reactivity against targeted TAAs was confirmed in 20/21 pts. Majority of response were detected by week 4 after 1st dose and as early as 2 weeks for some pts. EO, EN, and ENB were well tolerated (max exposure EN 68 wks, ENB 30 wks) with EO associated toxicity limited to local administration site reactions (48%; grade 1-2). The frequency and severity of nivolumab- or bevacizumab-associated AEs was consistent with historical monocompound experience. With a median follow-up of 9.3 months (range, 2.8-15.6), median progression-free survival (PFS), survival at 6 months (OS-6) and at 12 months for EN (C1+C2a+C2b) were 1.8 months (3 ongoing at 5.9, 7.1, and 14.7 months), 85%, and 50.1% (19/29 alive), respectively. With a median follow-up of 3.7 months (range, 2.2-7.2), pts on ENB (C3) have median PFS and OS-6 of 5.5 months (7 ongoing), and 80% (10/11 alive), respectively. ORR for EN and ENB were 10% and 36%, respectively (5 of 7 ongoing). In C2a, 12/23 pts stopped treatment due to neurological symptoms and PD on first MRI (median 5 wks, range 2-8). In C3 (ENB), only 1/11 pts stopped early due to PD. Conclusions: EO2401 generated strong systemic immune responses and was well tolerated in combination with nivolumab +/- bevacizumab. The addition of bevacizumab to EN improved PFS while survival across treatment cohorts is pending ongoing follow-up. To prolong EN exposure that is likely required for therapeutic activity in recurrent GB, the trial has been expanded with additional pts to evaluate low-dose bevacizumab (5 mg/kg q2 wks up to x 6) for early progressive neurological symptoms. Clinical trial information: NCT04116658.